McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.
Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.
EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)
Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.
Evaluation
The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.
For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.
Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
Consequences
An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).
Treatment
The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.
In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.
PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.